GB2522412A - Antimicrobial peptidomimetics - Google Patents

Abstract

Peptidomimetics of formula (I) may be useful for treating bacterial infections. R1 is H, acyl, carbamoyl, alkylaminocarbonyl or dialkylaminocarbonyl; R2 is optionally substituted alkyl, aralkyl or heteroalkyl; R3 is optionally substituted alkyl, aralkyl or heteroalkyl; R4 is optionally substituted alkandiyl, alkendiyl, alkyndiyl, cycloalkandiyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, alkylaryl or alkylarylalkyl; n is 1-4, m is 0 or 1. R2 or R3 may be CH2-biphenyl or CH2-naphthryl. The Peptidomimetic may be Bip-Arg-Bip-argmantine.

Description

Antimicrobial Pptidomimetics

Technical Field c

The present invention relates to compounds; compositions, and methods for treating diseases and conditions. In particular, the invention relates to compounds, compositi. one, and methods for treating bacterial infections, disorders and corid.it ions The invention further relates to a compouna of the formula (I)

H H

HN N N N H) m 0) 0 NH2 is wherein itt represents hydrogen, acyl, alkylaminocarbonyl or dialkylaminocarboriyl; it2 represents optionally substituted alkyl, aralkyl or heteroaralkyl; it3 represents optionally substituted alkyl or aralkyl or heteroaralkyl; it4 represents optionally substituted alkandiyl, alkendiyl, alkyndiyl, cycloalkyldiyl, alkylcycloalkyl, alky1cycloa1kylalkl, aryl, alkylaryl, alkylarylalkyl; a is 1, 2, 3 or 4; and mis Con; and to pharmaceutically acceptable salts and solvates of each of these compounds and to processes for the preparation of, compositions containing and the uses of such cømpounds.

Background

In 2011, there were 80,000 cases of invasive Meticillin resistant Staphylococcus aureus (MRSA) infections in the United States, resulting in 11,000 fatalities (Chan et at.

Chemical Biology and Drug Design. 2013, 82, 418-428). The emergence of multi-drug-resistant bacteria and the lack of new antibiotics in the drug development pipelines of phannaceutical companies is a major health concern (Butler et al., Journal of Antibiotics. 2011, 37, 413-425). Since 2000, only four antibiotics with new chemical scaffods were launched; the (i) oxazolidinone Linezolid (2000), (ii) lipopeptide Daptomycin (2003), (iii) pleuromutilin Retapamulin (2007) and (iv) macrocycle Fidaxomicin (2011) (Wright., Chemistry & Biology. 2012, 19, 3-10). Hence, there is an urgent need to develop new classes of antibactenials against emerging multi-drug-resistant bacteria (Projan. Drug Discovery Today. 2008, 13, 279---280.; Cooper and Shlaes Nature. 2011, 472, 32).

Sumnary S Novel cornpoi.nds have now been found with potent bactericidal activities with an unknown mechanism of action -Advantageously, according to the present invention there is prov Lded a compound of formula (1) H2N\ .NH 9 3 9 0 R

H HI I-I

RlHN m

F-IN

I

HN (I)

where in Ic represents nydrogen, acv, careamoyi, akylamnocarhonyi IS or dialk.ylaminocarbonvl represents optionally-substituted alkyl, aralky]. or heteroaralkyl; represents optionally substituted alkyl, a:ralkyl or he.teroaralkyl; P4 recresents optionally substituted alkandiyl, alkendiyl, alkyndlyl, cycloalkyidlyl, alkylcycloalkyl, aikylcycloalkylalkyl or al.kylaryl ri. is:L, 2, 3 or 4; and S m is C or 1; and to pharmaceuticaliy acceptanle salts arid solvates of eac.h of these compou.nds and to processes for the preparation of, compositions containing and the uses of such compounds According to a second aspect of the invention, it has been found that the compounds of formula (1) are obtained by the following process: Compounds of the formula (I) :15 H2N NH rn C 0

I

H N

in which it to P4, m and n have the meaning given abave are obtained when compounds of the formula (II) (t-BocHN \\ N(tBoc) (Pbf)HN N H in fl H NH NH9 0 (I:t:) in which. a, R, m and a have Lhe meaning given above are reacted in the oresen0c: of an amide/pepride couplinci reagent: with compounds or: the formula (Ii FmocR1 N R (III) wherein R' and R2 are defined as mentioned above, and deprotection with an acid, Conpouiads of the formuta (II) are obtained by reacting conic'ounds off the forimila (IV) NH(Fmoo)\*t%t0 rn 0 (Iv) wherein R3, R4 and ci are defined as mentioned above are reacted with a compound of the formula (V) (Fmoc)HN \CO0H HN,NH NH(Fbf) (v) wherein a is defined as mentioned above in the presence of a an arnide/peptide coupling reagent.

Compounds of the formula (IV) are obtained when compounds of the formula VT) (t43OC)HN\\\N(tB) m / .L / wherein R4 and a are defined as mentioned above.

S are reacted in the presence of an amide/peptide coupling reaqent with compounds of the formula (VJ I) (Frnoc)HN.

wnerein. R3 is defined as mentloneci above, Compounds of the formula (Vi) are obtained when a diamine of the formula(VIII) i-S HN. NH2 %%

R

V,L,L wherein N4 is defined as mentioned above and in is a is reacted with N, N'--di -Boc--S'methyiisothiourea -Compourvia of the formula (VI) wherein m is 3 can he obtained as known from the chemical literature, According to a third aspect of the invention it has been found that the novel compounds according to the inventlon are very S effective as antihactenials, advantageously also showing potent bactericidal activities against NF.SA. The invention provides a method of: treatinq a disease: disorder or condition, wherein the disease, disorder or condition is a bacterial inf action, such as for instance a skin infe.ct ion (e.g. boils), a respiratory disease (e.g. sinusitis, pneumonia) food poisoning or any other life-threatening systemic disease: in a subject in need of such treatment, comprising administerinc to said subject a compound of the formula (I) cr pharmaceutically acceptable salts and ccl yates thereof.

In a fourth asect of the invention, the present, invention is directed to the use of a c.om'oound of formula (I) or pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for toe treatment of a disease, disorder or condit: ion selected from any bacterial infection, such as f-or instance a skin infection (e.g. boils) , a respiratory disease (e.g. sinusitis, pneumonia) , food poisoning or any other life-threateninc' systemic disc se.

In a fifth-aspect of the inver::ion, the invention is. directed to the use of a compound of formula (1) -or pharmaceutically acceptable salts and solvates thereof for use in treating a bacterial infection.

The invention is directed in another aspect to the use of a compound of formula (I) or pharmaceutically acceptable salts arid solvates thereof in the manufacture of a mcdi cament for the treatment of a bacterially caused disease. disorder or condition -Another aspect of the invention is directed to a pharmaceutical composition comprising a compound of formula hE) or pharmaceutically acceptable salts and solvates thereof, and a pharmaceutically acceptable excipient.

Other arid further ispects will occur to those skilled in the

art in light of this disclosure.

Definitions The following are some definitions that may be helpful in understanding the description of the present invention. These are intended as general definitions arid should in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following

description.

Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements clearly encompass both èingular and plural forms of the recited integers, steps or elements.

Throughout this specification, unless the context

requires otherwise, the word "comprise", or variationi such as "comprises" or "comprising", will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification, the term "comprising" means "including principally, but not necessarily solely".

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.

As used herein, the term "alkyl group" includes within its meaning monovalezt ("alkyl") and divalent ("alkylene") straight chain or branched chain saturated aliphatic groups hav!ng from 1 to 10 carbon atoms, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example, the term alky]. includes, but is not limited to, methyl, ethyl, 1-propyl, isopropyl, 1- butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1,2-dimethylpropyl, 1..1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3- cnethylpentyl, 2, 2-dimethylbutyl, 3,3 -dimethylbutyl, 1,2-dimethylbutyl, 1,3 -dimethylbutyl, 1,2, 2-trimethylpropyl, 1,1, 2-trituethyipropyl, 2 -ethylpentyl, 3 -ethylpentyl, heptyl, l-methylhexyl, 2, 2-dimethylpentyl, 3, 3-dimethylpentyl, 4,4- dimethylpentyl, 1, 2-dimethylpentyl, 1,3 -dimethylpentyl, 1,4-dimethylpentyl, 1,2, 3-trimethylbutyl, 1,1,2 -trimethylbutyl, 1,1,3 -trimethylbutyl, 5-methyiheptyl, 1-methylbeptyl, octyl, nonyl, decyl, and the like.

The term "alkenyl group" includes within its meaning monovalent ("alkenyl") and divalent ("alkenylene") straight or branched chain unsaturated auiphatic hydrocarbon groups having from 2 to 10 carbon atoms, eg, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and having at least one double bond, of either E, Z, ais or trans stereochemistry where applicable, anywhere in the alkyl chain. Examples of alkenyl groups include but are not limited to ethenylr vinyl, allyl, 1*-methylvinyl, 1- propenyl, 2 -propenyl, 2-methyl-l-propenyl, 2-methyl-i- propenyl, 1-butenyl, 2-butenyl, 3-butentyl, 1,3-butadienyl, 1- pentenyl, 2-pententyl, 3-pentenyl, 4-pentenyl, 1,3- pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methy].-2- butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4- hexadienyl, 2-methylpentenyl, 1-heptenyl, 2-beptentyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, and the like. * The term "alkynyl group" as used herein includes within its meaning monovalent ("aikynyl") and divalent ("alkynylene") straight or branched chain unsaturated aliphatic hydrocarbon groups having from 2 to 10 carbon atoms and having at least one triple bond anywhere in the carbon chain. Examples of aJ.kynyl groups include but are not limited to ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, l-methyl-2-butynyl, 3-methyl-1-butynyl, l-pentynyl, 1-hexynyl, methylpentynyl, 1-heptynyl, 2-heptynyl, 1-octynyl, 2-octynyl, 1-nonyl, 1-decynyl, and the like.

The term "cycloalkyl" as used herein refers to cyclic saturated aliphatic groups and includes within its meaning monovalent ("cycloalkyl"), and divalent ("cycloalkylene"), saturated, monocyclic, bicyclic, polycyclic or fused polycyclic hydrocarbon radicals having from 3 to 10 carbon atoms, eg, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, 2-utethylcyclopropyl, cyclobutyl, cyclopentyl, 2-methylcyciopentyl, 3-methylcyclopentyl, cyclohexyl, and the like.

The term "aryl" as used herein refers to monovalent ("aryl") and divalent ("arylene") single, polynuclear, conjugated and fused residues of aromatic hydrocarbons having from 6 to 10 carbon atoms. Examples of such groups include phenyl, biphenyl, naphthyl, phenanthrenyl, and the like.

The term "acy]." is intended to mean a -C(O)-R radical, wherein R is an obtionally substituted C1-C3-alkyl, C2-C20-alkenyl, cycloalkyl having 7 to 7 carbon atoms, or aryl having or 10 carbon atoms, or a 5 to 6 ring membered heterocycloalky]. or heteroaryigroup having 1. to 3 hetero atoms select from N,S, or 0.

The term "heteroaromatic group" and variants such as "heteroaryl" or "heteroarylene" as used herein, includes within its meaning monovalent ("heteroaryl") and divalent ("heteroarylene"), single, polynuclear, conjugated and fused aromatic radicals having 6 to 20 atoms wherein 1 to 6 atoms are heteroatoms selected from 0, N, NE and S. Examples of such groups include pyridyl, 2,2' -bipyridyl, phenanthrolinyl, quinolinyl, thiophenyl, and the like.

The term "halogen" or variants such as "halide" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine.

The term "heteroatom" or variants such as "hetero-" as used herein refers to 0, N, X'1H and S. Th term "áralkyl" as used herein, includes within its meanLng ("aryl") and divalent ("arylene"), single, polynuclear, conjugated and fused aromatic hydrocarbon radicals attached to d.ivalent, saturated, straight aad branched chain C-C6-alkylene radicals.

The term "heteroaralkyl" as used herein, includes within its meaning monovalent ("heteroaryl") and divalent ("heteroarylene"), single, polynuclear, conjugated and fused aromatic hydrocarbon radicals attached to divalent saturated, straight and branched chain C-C6-alkylene radicals.

Preferably the aryl or arylene in the aralicyl has 6 or 10 carbon atoms Preferably the heteroaryl or heteroarviene i the het.eroaral).yl fo:rmsa five or six membered rent having 1 to.3 hetero atoms selected from N, S or 0.

The tern "oPtionally aubstituted" as used herein means the group to which this Loris refers may he unsubsti:uted, or may be substituted wi.th one or more grouis independently selected from C-Calkyl, C2--C5--alkenyl, C2--C--alkynyl, thio--C1--Cc,aikyl, C3--C8--cycloalkyl, Cr-C-cycloalkenyl, five to six memberedheterocvcloaikyi, halo, --COOP, --CONH,, C-, -C6-carhoxvl, halo-C--C-alkyl, halo-C2-C-alkynyl, hydroxyl, C--Cy-alkoxy, thio-C1C-alkoxy, C-C-alkenyloxy, halo-c--c:6alkox1,, halo-C2- C-aUcenvlox-y, nitro, amino, nitro-C1-C--alkyl, nitro--C2--Cr-- a.Lkenyl, ni.tro-C2-C-a1Jcynyi, five to six ring membered nitro-heterocvclvi, C1--Ccalkylamino, di -C--C1-alkviamino, C2 alkenylamine, C-C6 -aikynylarnino, CiCacyl, C-C--alkenoyl, C2-C6-aikynoyl, C--C4-acyiamino. di--C--Ccacylamino, C1-C--acyloxy, C,--C--alkylsulfonvlo:y. five to six nut membered heterocycloxy, five to six ring membered heterocycloamino, five to six ring membered haloheterocycloa:lkyl, a.kylsulfenvl, h-Ct-alkylcarbonyloxy. C2-Ccalkylthio, C1-C-acylthic, phosphorus-containeng groups such as phosphono and phosphinyl. aryl having 5 to 10 carbon atoms, five to six ring menibered heteroaryl, C1--C4--alkylarvl having 5 or 10 carbon atoms in thearyl, fl-a to six ring memhered C:t alk.ylhet.eroarvl, cyano, cyanate, isocyanate, --C (0) NH (C1---C--- alkyl) , and -C (0) N (C1--C-alkyi) 2-The present invention includes within its scope all isomerec forms of the compounds disclosed herein, including all diastereomeric isomers, racemates and enantiomers, unless the stereochemistry is-fixed in the fort ula drawing. Thus, formula () should be understood to include, for example, 2, cia, trans, CR) , (5) , Kb) , (I)) , (÷) , and/or (--) forms of the compounds, as appropriate in each case, unless the stereochemistry is fixed in the formula drawing. 1.4

The term Emoc" or finoc" in the formulas and descriotion refers to a tyicical fiuorenylmethyloxycarhonyl. protecting group.

The term "tBoc" or Eoc" in the formulas and description refers to a typical L--hutoxycarboriyi protecting group.

The term Rbf" stands for a 2,2.4.6,7 pent amethyldihydrobenzofuran-5 -suifonyl protecting group.

The te:cm "a compound of formula (IT) or pharmaceutically aocctehl a salts or solvates thereof" or "a c.ompound of form.ula(I5 or a pharmaceutically acceptable salt or solvate thereof" is intended to identify a coinpounci selected ftom the roup cc.nsistlno of: a compoun.d of the formula (I) , a pharmaceutically acceptable salt of a compound of formula (I) a pharmaceutically acceptable solvate of a cor'vound of formula (1) or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of a compound of formula (I) Thc term "therapeutically effective" is intended to quarifv the amount of compound c:roharrnaceutical composition or the combined amount of actIve ingredients in the case of combination therapy.

The term "treatment" as used herein to describe the present invention und unless otherwise qualified, means administration of the compound, pharmaceutical composition or combination to effect preventive, palliative, supportive, restorative or curative treatment.

The term "preventive treatment." as used herein to describe the present invention, means that the compound.

pharmaceutical cornposit.on o-r combination is administered to a subiect or member of a population that is sinnificantly predisposed to the relevant condition.

The term "palliative treatment" as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject to remedy signs and/or symptoms of a condition, S without necessarily modifying the progression of, or underlying etiology of, the relevant condition. Non-limiting examples include reduction of pain, discomfort, swelling or f ever.

The Srut "supportive treatment" as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject as part of a regimen of therapy, but that such therapy is not limited to administration of the compound, pharmaceutical composition or combination.

The ten "restorative treatment" as used herein to describe the presezit invention, means that the compound, pharmaceutical composition or combination is administered to a subject to modify the underlying progression or etiology of a condition.

The term "preventive treatment" as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject for the purpose of bringing the disease or disorder ino complete remission, or that the disorder is undetectable after such treatment.

The term "MIC" as used herein, means the minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation.

The term "compounds of the invention" or "a compound of the invention" as used herein unless otherwise specified, means a compound of formula(I) or a pharmaceutically acceptable salts or solvents thereof.

Detailed Description of the invention

Non-limiting examples of the above compounds according to the first aspect will now be disclosed.

S The comnounds of tb.e invent ± on may cxi st sri a cont±nu.um of solid states ranging from fully amorphous to fully crystalline -compounds of the invention may also exisc in both unsctvat.ed and solvated forms. The term solvate" is use!d herein to describe a molecular complex comp:cisin; the compound of the invention and a stochinmetric amount of one or mote pharmaceutically acceptable solvent molecules. The term "hydrate" is employed when said sd v cot is water -Compounds cf the pres cot inventeon can form af.dit ion salts, reaction of the amino substituent of formula (I) with a suJtai)le acid. Pharmaceutically acceptable salts of the compounds of formula (I) inc:Lude the acid salts addition of thorn.

It. ha- iow been found that a compound of the formula (I) or a pharmaceutically acceptable salt and solvate thereof is particular useful for the treatment of diseases, disorders or conditions caused by bacteria.

Examnles of such diseases or disorders are mentioned above The compounds of the invention show a particular surprising hind activity against the bacteria selected from Staphylococcus aureus Streptococcus Pyogenes, and Streptococcus prieumoniae.

The compounds are effective in comnacang the bacteria at surprisingly low nicromolar levels such as 25 M or less measured as D'IIC values. MIC values of about. 3 M have been obtained The compounds are bactericidal against Gram-positive bacteria inc:tuding Staphylococcus aureus strajns!FCC 33591, 29213 and RN 4220.

For administ rat ion to human patients, the totai daily doso of a compound of the invention is typically in the range of 3. to 2 grams, out is no:: tlmttea o:nau range oependinq on the mode of administration. The total daily dose may he administered in single or divided doses, and may at the :phystc-ians discretion., fail outside of the-typical range Administrationc an be oral or parenteral or otherwise, :E:n the pharmaceutical c-0000sltlon of the compounds of: the.

invention excipients can be used. The cern "excipient" encompasses diluents, carriers and adjuvants.

If the compounds are administered in tablets such as for example tscloseo in Tablets, Vol. 1, by H. Liberman and L. Lachoan (Marcel Deicker,New York, 1980) -The comnounds of-the invention may also he administered directly into the blood stream., into muscle or into an internal org an. suitable means for parenteral administration include int.ravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraureathral, intrasternal, .ntrccranial, intramuscular and subcutaneous. Suitable devices for pare-nteral administration include needle inj ectors, needle free inj ectors and infusion techniques.

The compounds may also be administered topically to the skin or mucosa, that is, dermalip or transdermal, The compounds or tue invention may also ne adminiscerea dii.:tly to the eye or ear, typically in the form of drop-s of micronized suspensinn or solution in isotonic, PH--adjusted.

sterile saline.

The formula (I) provides general definitions of the compounds according to the invention. Preferred substituents or ranges of the radicals given in the formula above and below are illustrated in the following: R' preferably represents hydrogen, C1-C20-alkyl-CO-, C2-C30-alkenyl-CO-, C1-C-alkyl-NH-CO-, or (C-C30-alkyl) 2-N-CO-.

R2 preferably represents optionally substituted C1-C12-alkyl, phenyl-C1-C4-alkyl, biphenyl -c1 -C4 -alkyl or anthracenyl -C-C4 -alkyl; R3 preferably represents optionally substituted C1-C12-alkyl, phenyl -Ci-C-a1kyl, biphenyl -C -C4 -alkyl or anthracenyl -C-C4 alkyl; a4 preferably represents optionally substituted C1-C2- alkandiyl, C2-C-alkendiyl, C2-C2-alkyndiyl, C3-C,- cycloalkyldiyi, C1-C6-alkyl -C3-C,-cycloalkyl, C-C6-alky1 -C3-C,- cycloalkyl-C1-C6-alkyl, C1-C6 -alkyl -phenyl or C1-C6 -alkyl-anthracenyl; n preferably is 1, 2 or 3; and m preferably is 1.

more preferably represents hydrogen, C1-C6-alkyl-C0-, C2-C6-alkenyl -CO-, C1-C16-alkyl-NE-CO-, or (C1-c16-alkyl) 2-N-CO-.

more preferably represents optionally halogen substituted C1-C12-alkyl, phenyl-C1-C2-alklyl, biphenyl-Q-C3-alklyl or anthracenyl-C1-C2-alklyl; more preferably represents optionally halogen substituted -alkyl, phenyl -C1 -C-alklyl, biphenyl -Ct -C2 -alklyl or anthracenyl-C-C2-alklyl; more preferably represents C2-C6-alkandiyl, C2-C6- alkendiyl, C2 -C5 -alkyndiyl, C3 -C, -cycloalkyldiyl, C -C6 -alkyl -C3- C,-cycloalkyl, Ci-C-alkyl-C3-d7-cycloa1kyl-c-c6-a1kyl, -C(COOH) -C1-C6-alkyl-, -C(CONH3) -C3H6-or C1-C6-alklyl-phenyl; n more preferably is 1, 2 or 3; and m more preferably is 1.

R1 most preferably represents hydrogen. or methylcarbonyl, with hydrogen being particularly being preferred; R2 moat preferably represents optionally halogen subitituted benzyl, biphenylmethyl or anthracenylmethyl; R3 most preferably represents optionally halogen substituted benzyl, biphenylmethyl or anthracenylmethyl; it most preferably proparxdiyl, butandiyl, pentandiyl, butendiyl, butyndiyl, cyclohezyl, -C(cOOH)-c3H-, -C(CONH2)-C3H6-or -cH2-Phenyl; n most preferably is 2 or 3.

The compounds of the formula(I) may be prepared according to the following process.

In a first reaction step known and commercially available diamines of the formula (VIII) are reacted with N,N'-Di-Boc-S-methylisothiourea in the presence of a base. This reagent is commercially available from Sigma/Aldrich. Bases can be customary acid acceptors such as tertiary amities, preferably N,N-disopropylethylamine. Suitable solvents include inert organic solvents such as hydrocarbons, preferably methylene dichioride (dichloromethane).

The reaction temperatures in this process step can be varied in a relatively wide range. In general the process is carried out at temperatures of 0 to 100°C, preferably 15 to 60°C, roost preferably at room temperature, When carrying out this process step the starting materials of formula (VIII) and the reagent are generally each employed in approx±mately equal amount. It may be beneficial to use the diamine of formula(V:uI) in excess to the reagent.

Work up is done bi customary separation methods, preferably flash chromatocraphy and evaporation of the solvents.

Ira sedond reaction step the obtained compounds of the formula (VI) are reacted with a coropourd of the formula (VII) -Compounds of the formula (VII) are known or can he prepared according to known methods. For instance one of such compounds is commercially available from Merck Millipore and CL Biochem China as "Fmoc--4 pheny1-phe-oH". Fmoc-4-ohenyl-L-phe.-oH" or "Fmoc-Bip-O}j" The amide/peptid.e coupling reagent can he customary coupJ.ing reacrents such as 2-(IH--Eenzotriazoie-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HETLI) Other suitable counli.ng reagents Include N, N --Dicyclohexvlcarbodii.niide (DCC) , (N, Ic I -DII sc:.propyicarbod ilmi de (PlC) , 1- [Bis (dimethvlaminomethylenej --lF-l, 2,3-triazolo [4,3- bi pyridinium I -oxid hexafluorophosphate (MATH) , 2-(6-Chloro-lH-benzotriazole--l-vl)-l,l,3; 3tetramethylaminium ho:xafluorophosphate (HCTIJ) , benzotriazol -I --yl -- oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) , 6-Ch:Lorc--benzotriazo.e-1-yloxy--tris-pyrrolid±nophosphorijum hexaflucrophosphate (Pyclock) or Ethyl 2 --Cyano-2- (hydroxyimino) acetate (Oxytna) . Prefer ably these coUpling reagents are used in the presence of a base such as for in. stance a tertiary amine, preferably N, N-Diisopropylarnine -The reaction temperature.s In this process step can be varted In a relative±y wicie ranoe. In general tne process:1.8 carried out at temperatures of 0 to:Loo'c, preferably 15 to GOT, most preferably aL room temperature.

When c:arrying out: this process step the starting materials of formula (VI) and the compound of formula (VII) each employed in approximately equal amount., It may he beneficial to use the compound of formula WI:) in small excess.

Work up is anne by customary separation methods preferably by washing steps and an evaj:oration of the solvent, Dissolution and further post-reaction with a base, such as I, 0-:Diazahicyclo[5.4.C]undec-7-ene (::BtJ) , at room temperature and flash chromatography is possible.

ma third reaction step the obtained compounds of the formula (IV) are reacted with a coat ound of the formula V) Compounds of the formula (V) are known or can be rrepared according to known methods. For instance one of such compounds is commercially available from Merck Millipore or Oh}3iochem as "Fraoc-Prg (Pbf) -OH" The amide/peptide coupling reagent can he customary coupling reagents such as 2-(1H-Benzotriazole-l--yl) -1,1,3,3-tetramethy..uronum hexafluorophosphate (H}3T13) Other suitable coupling reagents include N, N' -Dicyclohexylcarbodiimide (DCC) , (N, N' -Diisopropylca.rbodiimicie (PlC) , K 1- IBis (dtmechylarnino) methylene] -IH--l, 2,3 -triazolo [4,5-n] plr_o1nun 3-ox_a nexaf luo:o,ho ahat e tCT 2-5 ChIoto 1H-benzot:ciazole -I -yl) -1,1,3,3-tetrameuhylaminium hexafluorophosphate (HCTtJ) , henzotriazoi-1-yl- o:x:ytripyrro1idn.opnosphoniurn hexaf luoroph.osphate (Pvsop) , £ -Chloro-benzotriazoie-l-yloxy--tris--pyrroi idinophosphonium he.x.afluorophosphate (Pyclock) or Ethyl 2-Cyano-2- (hydroxyimino) acetate (Oxvma) , Preferably tuese coupling reagents are used in the presence of a base such as for instance a tertiary amine, preferably N, N-i:.iisor:ropyla.minc?.

Suitable solvents include inert organic solvents such as dimethvloramide The reaction temperatures:Ln this process step can he varied in a relatively wide range. In general the process is S carried out at temperatures of 0 to 100°c, nreferahiv 15 to 60°C, most: prereracly at room temperature when carry:Ln.q out this process step the starting materials of formula (IV) and the cow.oound of formula (V) are generally each employed in approx.imately equal amount. It may he beneficial t.o use the compound of formula (1) in excess.

Work up is done by customary separation methods, pref eraniy rw washing steps and an evaporatron of the solvent.

Disco lution and further txst reaction with a base; such as 1, 8--Diazabicyclo [5,4.01 undec-7--ene (P1-30) , at room tetr.perature and flash chromatography is possible.

in a fourth reaction step the obtained compounds of the formula. (II) are reacted with a compound of the formula (III) compounds of-the formula (III) are known or can be prepared accordir.g to known methods, For instance one of such compounds is commercially available from Merck Millipore or GE]Siochem as "Fmoc-4-phenyl--Phe-OH" or "Fmoc-Eip--0Ei".

The amide/p;eptide coupling reagent can he customary coupling reagents such as 2-(lH-Eenzotriazole--l-yl) -:L, 1,3.3-tetram.ethylu:ron:Lum he.xafluorophosphate (1-12Th) -Ocher suitable coupling reagents include N, N -Dcyclonexylcarbodl imide (Dcc), (Lu, N -Diisoprolcarbodiimide (PlC) , (1- [Bis (dimet:hylamino) methylene] --1H--L, 2,3 -triazolo [4, 5-- hi p'yridinium:3 -oxid hexafluorop:hosphate (HATU) * 2-(6-chloro-lH-b-enzotriazole--l-yl) -1,1,3. 3-tetramethylaminium hexafluorophosphate (HCTTJ) , henzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluoror-hosphate (PyBop) , 6--chloro--benzotriazole-1-ylcxy-tris --pyrrolidinophosrhonium hexafluor-ojthosphate (Pyclock) or Ethyl 2 -Cyano-2 - (hydroxyimino) acetate (Oxyma) . Preferably these couplinci reagents are used. in the p:resenceof a base such as for instance a tertiary amine, preferably N, N-Diisopropvlamine.

Sin c.abe solvents include inert: organic solve:nt s such as dimethylformamide.

The reaction temperatures in this process step can he varied in a relatively wide range. In general the process is carried out at temperatures of 0 to 100 °C, preferably 15 to 60°C, most. preferably at-room temperature When carrying out this process step the starting materials of formula (IV) and the compound of formula (V) are generally eacn employed.Lnapproxsmately equal amount, It may he beneficial to use the compound of formula (V) in excess.

Work up is done by customary separation methods.

preferably by washing steps and an evaporataon of the solvent.

Dissolution and further post-reaction with a base, such as thazahicycloundecene (DLVI) at. room temperature and flash -chromatooraphy is possible.

Finally a precursor of the compounds of formula (I) is obtained of the formula (Is) (t-Boc)HN 0. \,,N(t-E3oc) * H H I H N N 7 N R N H) in H 1! 0 0

HN

--N(PBf) /

HN nfl Lu (Ia)

Compounds of the formula Ia) are novel and as such part of the instant invention.

The compounds of the formula (I) can be obtained from the compounds of formula (Ia) by reaction with a strong organic acid such as trifluoroacetic acid. Such organic acids must be able to remove the Pbf and 3oc moieties.

The reaction temperatures in this process step can be varied in a relatively wide range. In general the process is carried out at temperatures of 0 to 100°C, preferably 15 to 60°C, most preferably at room temperature.

Work up is done by customary separation methods, preferably by evaporation of the solvent, re-dissolution, chromatography and HPLC.

Other compounds disclosed herein also may be synthesized utilizing known methodologies disclosed in texts well known to those skilled in the art such as Amino acids, Peptides and Proteins in Organic Chemistry, Ed. A. B. Hughes, vol. 4.; Wiley-VCH, Germany, 2011.

Examples

Example 1: Preparation of BipArg--Bipagrnantine H2N

-U ---Cl /

-f4f I\-' I 7

H NH

4*\ ../ i Fvn.ie: 0.4 44i.iCi çs-'-Moiiar V qht:. fl2 771H8 Step 4--Diaminobutane (0.6 mmcl, 44 rag) , N, N-di --(t--butoxycarhonyl) -S-raethylisothiourea (0. 4 mmci, 116 mg) and N,Ndiisoropylethiamine (DIPEA; 1 mmci, 175 L) were 1.0 dissolved in anhvdrous 0312012 (6 mU) The mixture was stirred at 25 °C, 16 h under N2 atmosphere and the resulting guarrylated amine was purified by flash chromatography using a CH,0l2/met.hanol grad:Lent and monitored. using MS. The solvent was removed in vacuo to give a colourless cii (79 ma, 0.24 mmcl, 60) Step 2: FTaoc-Bip-O-I (0.264 inmo 1) , HBTCJ (0.49 mmcl) , DIPEA (0.72 mmcl) and dimethylformamide (DM5, 10 mL) were added to the oil and the mixoure was at Lured s.t 23 0 5cr i h, Step 3: The contents were dissolved in ethyl acetate (30 ml.) and washed with brine (50 mL) thrice. The organic phase was removed in vacuum to give a yellow gel which was dissolved in S CH2C12 (10 mIs) Step 4: DBU (0.36 mmol, 54 ML) was added to the mixture and stirred at 25 °C for 1 Ii. The intermediate was purified by flash chromatography using a cH,Cl,/methanol gradient monitored using MS. The solvent was removed in vacuo to give a colourless oil (0.20 mmol, 83 %).

Step 5; Fmoc-P.rg(Pbf)-OH (0.264 mmcl), HBTU (0.48 mmol), DIPEA (0.72 mmcl) and dimethylformamide (DMF, 10 aL) were added to the oil and the mixture was stirred at 25 °C for 1 h. Step 6: Steps 3 and 4 were repeated for Fmoc removal.

Step 7: Step 2 was repeated.

Step 8: Steps 3 and 4 were repeated for Finoc removal.

Step 9: TFA: cx2ci2 (1.5 ml., 95:5 v/v) was ad4ed to Bip-Arg(Pbf)-Bip-agmatine(Boc)2 and stirred for 1 h at room temperature.

step 10; Excess TFA: CH2C12 was b:own off using a gentle N2(g) stream to yield a yellow oil. The oil was re-dissolved in MeOH and purified by HPLC (water and acetonitrile solvent) retention time -16.5 mm, to give the target product (Bip-Arg-Bip-agmatine; 3kB-Ag; ETC-2016975) as a white powder (4.1mg, 0.006 mmol, 6% overall yield).

The electrospray ionization-mass spectrum (ESI-MS) shows three characteristic peaks at 367.5 [M+2H]2, 733.4 [M+H]" and 755.4 LM+NaY.

The mass spectrum is shown in Figure i.a.

NMR Spectral data: H NMR (400 MHz, CD3OD) 8 1.20-1.77 (811, rn), 2.75-3.24 (1OH, rn), 4.07, 4.33, 4.49 (114, m, a-Es), 7.10-7.52 (18K, m, aromatics); c NMR (100 MHz, CD3OD) 824.6, 25.6, 26.0, 28.9, 36.9, 37.5, 38.3, 40,5, 40.7 (methylene Cs), 52.9, 54.0, 54.8 (a-Cs), 126.3 (x2), 126.5 (x2), 126.6 (x2), 126.9, 127.1, 127.2 (x2), 128.4 (x2), 128.5 (x2), 129.5 (x2), 129.7 (x2}, 132.9, 135.8, 1396, 140.3, 140.4, 140.6 (aromatics), 157.2, 157.3 (guanidinium), 168.3, 171.4, 171.9 (C=O).

The H and 3C NMR spectra are shown in Figures lb and lc respectively.

Example 2: Proposed Scheme for solid-phase synthesis (24 step) 1. Anchor Fnioc-Bip-OH (5.0 mmol, Seq.) to 2-chiorotrityl chloride resin (1.0 rnmol scale) with DIflA (5.0 mmol, Seq.) in CH3C12 (10 mL) for 60 mItts.

2. Filter off excess solvent/reagents and wash resin with CH2Cl2 (-lOmi x 2), CE3OE (-lOml x 2) followed by DMF (-torn]. x 2).

3. Remove Fmoc using piperidine: DMF (20% v/vJ with stirring and microwave (40W, 65 °C, S mm).

4. Filter off excess solvent/reagents and wash resin with 1DM? (-. total x 2), cH3OH (-total x 2) followed by DMr (- 1Cm]. x 2).

5. Dissolve Fmoc-Arg(Pbf)-OH (5.0 mniol, 5 eq.), HBTU (5.0 initial, S eq.), DIPEA (5.0 mntol, S eq.) in 1DM? (10 rat) and allow this mixture to react with the resin and microwave (40W, °C, 10 rain) 6. Filter off excess s3lvent/reagents and wash resin with 1DM? (-lOft]. x 2), CH3OH (-loin]. x 2) followed by 1DM? (-.

lOm]. x 2) 7. Repeat step 3, 8. Repeat step 4.

9. Dissolve Fmoc-Bip-OH (5.0 mmcl, S eq.), UBTU (5.0 mmol, 5 eq.), DIPEA (5.0 inmol, 5 eq.) in 1DM? (10 niL) and allow this mixture to react with the resin and microwave (40W, 65 °C, 10 mm) 10. Repeat step 4.

11. Repeat step 3.

12. Repeat step 4.

13.. Dissolve Boc2O (Boc-anhydride; 5.0 mmol, S eq.) and DIPEA (5.0 mmol, 5 eq.) in DMF (10 niL) and allow this mixture to react with the resin and microwave (40W, 65 °C, 10 miii).

14. Filter off excess solvent/reagents and wash resin with 1DM? (-lOml x 2), CH3OH C-total x 2) followed by Ck32C12 (-tOtal x 2) :L5. Add l0 acetic acid in CH2C12 (v/v) to the resin aria.

stir (RT 50 mm.) 16. FilLer the mixture and neutralise the so.ution with NaHCO3 until no effervescence is seen.

17, add CH2C12 and brine. The orqantc layer was concentrated in vacuo to yield crude Bip-Arg(Pbf) -Pip-OH as a vellcw oil.

18.. React I, 4-di.anrimobutane (2 omol, 2 eq) with l his (ce butoxvcarbonvi)-2 -methyl -2 -thionseudourea (I mmol) and DIPEA (5 mmo]., Seq.) in 0H2*c12 for GO rains.

19. Purify the m:Lxt.ure with flash chromatography using hexane, EtOAc, OH2Cl2 and CN2OH to obtain NH2-(CR2) 4-guanidlne (Boo) ,, as a white solid.

20£ Mix crude Bip-Arg(Phf) -Pip-OH with NH2-(CE1) guanidine(Boc)2, EDO (1.2 rarnol) and HOEt (1.2 mmci) in DMF (5 oh) and allow this mixture to react overnight, at RT.

21. The reaction mixture was extracted using ethyl acetate/brine and the organic layer was concentrated In vacco to yield a yellow oil.

22. Remove the Soc and Phf with TEA and two drops of water us.ng microwave (40w, 65 cio mit) 23. Excess TEA was blown off with a N2 gas stream (-20 mm for 1 raP) to yield the crude target as a yellow oil, 24. .urify the yellow oil with C Reverse Phase xarnpie 3: BIo1oica1 activity Th.e conround of the working example has neen tested fc:':r biological activity in the following assay: Elsinc a sterile loon, 3 to 5 isolated colonies of bacteria of the same morc)horogical appearance are selected from the overnight agar plate -The colonies are transferred into a conical flask containing 5 ml of liquid medium (i.e. I'hieller-Hinton broth) . The broth is. incubated at 37°C in a shaker at 220 rpm u:utii it reaches a turbidity that is equal to the turbidity of a Mcfarland Standard 0.5 (correspond to 1x108 ofu/ml) . This culture growth ste-p will require 1-2 hours dependinc on the bacteria tested.

Durine this reuse period, an antibacterial dilution is prepared. Therefore an antibacterial stock solut:Lon isciiluted in Mueller-Hinton broth, The concentration of DM90 is kept at 5%. 100 p1 of the antibacterial solution are dispensed into the first well of a row. 50 /11 or medium c-ontainincj 0.3% of IJNSO are dispensed to the rest of the wells. I 2-fold serial dilution is achieved y transferring 50 p1 from the first well (containing the highest concentration of antibacterial) into the second well, and continuing like this until the lath well in the row. The final 50 ul are discarded so that every well has 50 p1 of each antibacterial dilution.

The 11th well was used as the growth control well (medium with bacterial inoculums no antibacterial.) while the 12th wei. was the sterility control well (medium only) . Table 1 illustrates a typical sample layout.

The bacterial suspension prepared above is mixed thorough:Ly, and diluted-by a factor of 1: 100 in the sterile medium. Each-well and the growth control well is inoculated with 50 tl of the bacterial suspension. This resulted in the final desired inoculums of 5 x 10b cfu/ml in each well. [0 the sterility control well 50 p1 of ste-rile medium are added in place of the bacterial suspension. 10 l aliquot from t.he growth control well is removed immediately after inoculating the p1 e and pipetted it into a sterile Eppendorf tube holding 990 p1 of sterile broth. It is mixed well by vortexing. This suspension i_s further diluted (1:13) by pipetring L03 p1 into 900-p1 of sterile broth and mixing it :u well, 100 l of each of the two dilutions are plated onto two different antibacterial--free agar plates. A sterile cell spreader is used to spread the liquid. Then the plate is sealed with a transrarent adhesive S The microtiter plate and agar plates are incubated at 37°C for 16-20 hr or until satisfactory growth is obtained.

The colonies on the agar plate are counted the n-ext day to verify that the right number of cfu was inoculated. The plate i agitated in the SpectraNax spectrcphotomet.er for:90s and the* On633 for all the wells in the plate is recorded.

Table 1: Typical plate layout for the setup of a 96-well plate for the cell-based assay.

Conr(u/m1) 1 2 3 4 1 6 7 8 9 10 1 S A Ceftazadir.o 2-fl0 00 u00 0.2b3 3125 0.05 3.0"] .Oa O.uflfi 0n4 r' fl a;:ni1r' Toi' E (L25' ])t O.'t.3 1. .015 0!E

__ ----__

La'te.o.d 1 flfl 5. 50 3. S --j I -*-...95 0 Q 3 n ----I -f --F t.1-e"od 1 5 00 t2.Sfl 31 2 7.-ct <5 -. . 0 9 0 241 GO -i ------.----___ ____ ____ -t-tm __ ----------------.---.-__

G I -

-----------------------l-------.4 -

H 1.5

GO: Growth control 8-C: Sterility control The compound showed an silo value of 3.125 usi, vs. MASA (ATCC 33591) ,S.aureus (RN 4220) , S. aureus (ATCO 29123) and 6. 25 aM vs. Strep. p.neuinoniae (ATCC 96:L9) and Strep. pyoaenes ARC 9.39) -In th.e S. aureus tests the cot pounrd h-ad a lower silo value than commercially available antibacterial compounds Linezolid and Daptomycin. In the Strep. tests it showed at least improvement over Daptomycin.

the compound also showed activity on H. faecalis but less so. 5.

Figure ld shows the bactericidal activity vs. S. aureus (ATCC 29213) at its respective MIC (compound of Example 1 on the left, Linezolid on the right) after dilution of the antibacterial. The picture on the left shows that upon treatment with the compound of Example 1 at its MIC, the bacteria remains dead even after the antibacterial was diluted, suggesting that it possessed a bactericidal mode of action. The picture on the right shows that upon treatment with Linezolid at its MIC, after the drug was diluted, the bacteria was able to re-grow, suggesting that Linezolid is bacteriostatic.

According to the processes of the invention or known metho4s the following other compounds have been synthesized and their MIC value vs. MRSA (ATCC 33591) and S. aureus (ATCC 29213) determined: No. R1 It2 It3 jR rnnMIc(MM) MIC(ttM) (ATCC (ATCC 33591) 29213) 1 H Bip Bip -C4H3 3.125 3.125 2 H -Bip tip -C4H8-6.25 not determin ed 3 H Bip tip -C5H-T 2 6.25 12.5 4 H tip Bip CHr T T so so 3:3 Bp Rip 1REu=c CH2 (trans) T:: Rip TcdoccH2:12 mrp-Rip T753i2c4 Th 2 5.25 6s

--

9 CHCO Rio Rip: 1 2 12.5 6.25 000H 11 H T7 Y iTT CONH, Rip stands for

S ji(Ni

K

Ant.h stands for It will he apparent that this arc various other modifications and adaptations ci trte invention will be appa:rent to the person skilled en the art after reading the S forecoing disclosure without departing from the spirit and scope of the invention and iris intended than all such modifications and adaptations come within the scope of the appended claims.

Claims (1)

1. Claims 1. A compound of the formula (I) R1HN)k)JH)HH N N H2-I N (I)wherein R' represents hydrogen. acyl, carhamoyl, alkylaminocarhonyl or dialkiaminocarbonyl; represents optionally substituted alkyJ., aralkyl or heteroaralkyl; represents optIonally substituted alkyl, aralky or ne:eroaralkyi; represents ciption.ai.ly substituted alkandlyl, alkendiyl, alkyndiy:L, ccloai]cidiyi, aikylcycloalkyl a.LkylcycuoalJcylaikyl, aryl, alkylaryl, alkyher ylaikyl; n is c, 2, 3 or 4; and a is Cc}r 1; ora pharmace.ut icaily acceptable salt and solvate of such C omc oii.nd.

   2. A compound of formula (I) according to claim 1 wherein AL renresents:rwdroqen, C1-C20-a1kyl<C, C2C-alkenyl-CO-, C1-C2aikLNH-CO-or (C-C23--clky1) A2 represents optionally substituted C1alkyl, phenyl C4alky1 biphenyl.-C1-C:4-alkyl or mnthracenyi--C1-C.-alkyl represents optionally substituted C1-C12--alkyl, phenylc1 C.L-alkyl, hiphenyl -C-C alkyl or anthracenyl-C*1-O-alkyl; represents optionally substituted C-C:2-alkandiyl, alkendiyl, C-C12-al]cyndivl, C3 C-cyc1oa1]cyldil. C -C--alkyl- C-C--oycloalkyl, C:L-C-alkyl--C-C-cvcloalkyl-C--Cc-alkyl. C-C-alkyl-phenyl or C1-C-alkyi-anthracenyl; nisl,2or3; and m is 1.

   3, A compound of formula (1) according to claim I wherein represents hydrogen, C1C1-alkyl-Co-. CC1.sal]cenylCO, C C-alkyi -N13CO-or (C -Cr-alkyl) ,N-CO * represents optionally halogen substituted 0r C12*-al1cyl, phenyl -CC2-alklvl, biphenyl --C1C:2alk.1yl or anthracenyl C1C.-alIclyl; :R3 represents optionally ha.oaen substituted C-C2alkyl, ohe,yl --C1--C-clnIyl. biphenyi--c1-c, --aiklyl or an:hracenyl C:C1 alkivi; P4 represents 02-C alkandlyl, C2C6a. lkendiyJ., C alkyndiyl, C3-C-cycloalkyldiy1, C., -C-alkyi C --cycloalkyl, C1-C6-alkvl--C3C7-*cycloalkyl-C1-c6-aikyl, --C (00031) -C1-Cr-aikyi- -C (CCIqH2) -CH--or C1*-C4*-alklyl -pheriyl; nisi, 2or 3; and 0 15 1.

   4. A oompourd of formula (I) according to claim 1 wherein represents-hvdroge:n or me thylcarhonyl; P2 represents ontionally halogen suhstitute.d henzyl, hiphenylmethyl or anthracenylmethyl; P3 represents opt:Lonallv halogen substituted hensyl, bip*henylmethyl or anthr:acenylrne:hyl; P4 represents propandiyl, butandiyl, pentandiyl, hutendiyl, hutynd±yl, cyclohexyl, -c (COCH) -C3}L-, -C (C0NH2) -C3H or Phenyl; n most preferably is 2 or 3; and m is 1 5, A process for making compounds of the formula (i) ft2 0 RiHN rn ( I H 0 0 /H N NH2HN (I)Sin which EQ1 to R, m and a have the meaning given In claiml are obtained when compounds of the formula (II) (t-Boc)HN NBoc) (Pbf)HN k1 N Ti H ( NH 0 (ii) in which!, R4, m and a have the meaning given above are reacted in the tresence of a base with compouncs of the formula (ii:!:) FmocR1 N R!IlT wherein R1 and Ti2 are defined as mentioned above, and deproteotion with an acid.

   S

   6. A comnound of the formula (Is) BocHN>NBoc R1 HNE H

   HN 7NH(Pbf) (Ia) NH wherein 1 2 -2 R4, m and n are defined as in claim I. 7. A compound of formula (1) according to any of claims 1 to 4 or pharmaceutically acceptable salts or solvates thereof for use as a medicament.

   8. A compound of formula (I) according to any of claims I to 4 or pharmaceutically acceotable salts or solvates thereof for use in the treatment of diseases, disorders and cot ditions which are a hacterial infection.

   9. Use of a compound of formula (I) according to any of claims 1 to 4 or pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from any bacterial infection.

   10. A method of treating a bacterial infection caused disease, disorder or condition in a subject in need of such treatment, comprising administering to said subject a compound of fonnula(I) according to any of claims 1 to 4 or pharmaceutically acceptable salts and solvates thereof.

   11. A pharmaceutical composition comprising a compoulid of formula (I) according to any of claim 1 to 4 or pharmaceutically acceptable salts and solvates thereof and a pharmaceutical acceptable excipient.